Trialkylsilyl-6-aminonicotinamides

ABSTRACT

A composition useful for relieving the symptoms of psoriasis in humans are disclosed. The composition is an N-trialkylsilyl-substituted 6-aminonicotinamide. The composition is applied in a suitable pharmaceutical base, such as a cream or ointment, to the affected area of skin.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds useful for the treatment ofpsoriasis through topical application to improve and heal the skinlesions of psoriasis in humans.

2. Description of the Prior Art

Psoriasis is a chronic disease, and remains a disfiguring and disablingcutaneous impairment to millions of persons. Its etiology is completelyunknown, and therefore, prevention remains inconceivable. Therapy hasnecessarily been empiric, and has included the systemic use ofantimitotic drugs such as methotrexate to induce remissions of thelesions. However, acute and chronic toxicity on tissues other than skinhas discredited use of methotrexate. Therefore, it is imperative thatother means of therapy be found for external delivery of drugs so thattoxicity is confined chiefly to the skin, or by the discovery of newdrugs having nontoxic attributes.

U.S. Pat. No. 4,067,975 discloses the treatment of psoriasis with afamily of 6-substituted nicotinamides, 6-substituted nicotinic acid andesters thereof and 2-substituted pyrazinamide or thionicotinamide. Whilesuch compounds have proven effective, their use must be accompanied bythe application of Vitamin B₃ to avoid possible hearing impairment inthe patient.

U.S. Pat. No. 3,920,840 discloses the treatment of psoriasis with one ofthe degradation products of mechlorethamine hydrochloride,N-methyldiethanolamine, a compound which is not primarily eitherantimitotic nor allergic.

SUMMARY OF THE INVENTION

Certain substituted 6-aminonicotinamides have now been discovered thatare particularly useful in the treatment of psoratic conditions, withoutthe type of toxic affects caused by prior art compounds.

The compounds of this invention are N-trialkylsilyl-substituted6-amminonicotinamides, substituted at other than the annular nitrogen.Either one, or both, of the hydrogen atoms in either, or both, of theamino groups may be replaced by a trialkylsilyl moiety. It is preferredthat the total number of carbon atoms in the alkyls be 24 or fewer andmore preferred that each alkyl include 4 or fewer carbon atoms. While upto four trialkylsilyl groups can be substituted (i.e., two at eachnon-annular nitrogen), it is preferred to include only a singletrialkylsilyl group at each nitrogen.

The substituted 6-aminonicotinamides of this invention are particularlyadvantageous because of their lower toxicity and greater solubility,particularly when utilized in a topical application as part of asolution, an ointment or a lotion.

DESCRIPTION OF THE SPECIFIC EMBODIMENT

The substituted 6-aminonicotinamides of the present invention are thosehaving the formula: ##STR1##

The trialkylsilyl groups (SiR₃) each contain three alkyl groups (R)which may or may not have the same structure. It is preferred that thetotal number of carbon atoms in all three alkyl groups not exceed 24. Itis more preferred that the alkyl groups be selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl and tert-butyl.

The compound may contain from one to four trialkylsilyl groups on thetwo non-annular nitrogens. Thus, both n and m are selected from thegroup 0, 1 and 2. While either m or n is always at least 1, it ispreferred that both m and n be equal to 1, i.e., the compound includesone trialkylsilyl group on each of the two nitrogens.

PREPARATION OF THE COMPOUNDS

The compounds of the present invention may be prepared in accordancewith the following equations: ##STR2##

In equation (1), 6-aminonicotinamide is dissolved in dry DMF by heat andallowed to cool. While still warm, triethylamine is added and theresulting solution cooled. After cooling, the triethylchlorosilane isadded and the solution is left to stand for a number of hours, typicallyovernight. The solution is then dried and the product removed byconventional means.

The bis-trialkylsilyl-6-aminonicotinamide obtained by equation (1) maybe further reacted in the presence of a strong base, typically butyllithium, to obtain a fully substituted compound as shown in equation(2). Of course, by limiting the amount of reactants, a compoundsubstituted at only three of the four locations will be obtained.##STR3##

PREPARATION OF THE THERAPEUTIC COMPOSITIONS

The compounds of the present invention are admixed in a conventionalmanner with commonly available bases such as alcohols, creams orointments. Both dimethyl sulfoxide (DMSO) and Aquaphor have been foundacceptable, although it is felt that the ability of DMSO to penetratethe skin may have an adverse effect on treatment. The followingconcentrations are preferred:

    ______________________________________                                                    Concentration.sup.1 Range                                         ______________________________________                                        Preferred      0.1 to 10%                                                     More Preferred                                                                              0.1 to 5%                                                       Most Preferred                                                                              0.3 to 5%                                                       ______________________________________                                         .sup.1 Weight percent N--trialkylsilyl6-aminonicotinamide in base.       

The therapeutic compositions are applied topically to the affected areaof the skin.

EXAMPLES

The following examples are illustrative of the synthesis of thesubstituted 6-aminonicotinamides of the present invention, and of theirutility in the topical treatment of psoriatic lesions. As will beobvious and understood, other compounds within the scope of thisinvention may be formed by selecting appropriate reactants andquantities. Thus, the examples provided should not be construed aslimiting the scope of the invention.

The following abbreviations have been adopted for use in the examples:6-AN (6-aminonicotinamide); DMF (dimethylformamide); Et₃ N(triethylamine); Et₃ SiCl (triethyl chlorosilane); BSA[bis(trimethylsilyl) acetamide]

Preparation of bis-trimethylsilyl-6-aminonicotinamide

0.51 g of 6-AN was stirred with 3.28 g (4 equivalents) of BSA for onehour at room temperature in a reaction flask. No reaction was observed.Thereafter, 1 ml of DMF was added and the mixture stirred for severaldays, after which time the 6-AN had gone into solution. The mixture wasthen transferred to a rotary evaporator connected to a high-vacuum pump,with two dry-ice traps. The reaction flask was gradually heated to 90°C. and after 4 hours, the residue in the flask had crystallized, while aportion of the crystal had sublimed on the upper portions of the flask.

The product was scraped from the walls of the flask and the fractionthat had sublimed, an intermediate fraction that was mostly sublimed andthe crystalline residue, were isolated. In all three cases, thestructure of the product was found to be ##STR4## and confirmed by NMRspectroscopy.

Preparation of bis-triethylsilyl-6-aminonicotinamide

2.06 grams (15 m moles) of 6-AN and 35 ml dry DMF were added to a 250 mlflask and heated under Argon until the 6-AN dissolved. After cooling,but while the mixture was still warm, 25 ml (180 m moles) of Et₃ N wasadded to form a cloudy solution which was cooled in dry ice. After 10minutes, 15 ml of Et₃ SiCl was added and the mixture kept in the dry icefor an additional 30 minutes. The mixture was left overnight at roomtemperature.

A filter, flask and funnel were dried under vacuum at 120° C. for 2hours. The slightly yellow reaction mixture was filtered through mediumsintered glass in a glovebox, rinsed one time with 10 mls of toluene,and stripped to dryness on a rotovap for one hour. Forty mls of tolueneand 5 mls Et₃ N were added to dissolve oils. The resulting solution wasfiltered through GF/F in a glovebox and stripped to dryness at 90° C.for one hour at 0.3 Torr. 5.06 grams of product (confirmed to bebis-triethylsilyl-6-aminonicotinamide by NMR) were recovered(theoretical=5.46).

Preparation of bis-t-butylsilyl-6-aminonicotinamide

2.00 grams (14.58 m moles) of 6-AN and 40 mls dry DMF were added to a100 ml flask and heated under argon until the 6-AN dissolved. Aftercooling to room temperature, 22 ml (158 m moles) of Et₃ N was added toform a first clear, then cloudy solution. Just before it became verycloudy, 13.6 grams of t-butyl dimethylsilylchloride was added, causinginstant precipitation. The mixture was left overnight at roomtemperature.

The next morning, the reaction mixture was almost pure white, with atrace of yellow. Toluene (20 ml) was added and the mixture cooled in dryice to approximately 0° C. After cooling, the mixture was filteredthrough medium sintered glass and stripped in a rotovap. Yield ofdesired product (confirmed by NMR) was 5.34 grams (theoretical=5.33grams).

Therapeutic Examples

The following examples are illustrative of formulations of compositionsaccording to this invention. Although the examples utilize a namedcompound, the examples are not intended to be limited to the specificcompound named, but any member of the above-described group of compoundsor combination thereof could be substituted therefor within the scope ofthis invention.

                  TABLE 1                                                         ______________________________________                                                                    CON-                                                                          CEN-                                              PA-    AREA                 TRA-                                              TIENT  AFFECTED    BASE     TION.sup.1                                                                          RESULT                                      ______________________________________                                        1      First dorsum of                                                                           DMSO     3%    Slight improve-                                    the fifth finger           ment in 4th                                                                   week.                                       2      Medium size A        1%    Lesion cleared                                     plaque below               completely with-                                   right knee                 in 4 weeks,                                                                   although slight                                                               recurrence                                                                    during 5th week.                            3      Plaque right                                                                              DMSO.sup.2                                                                             1%    Mostly cleared                                     forearm     Corn           in 3 weeks,                                                    Oil.sup.2      complete clearing                                                             after discon-                                                                 tinued treatment.                                  Plaque lower                                                                              A        1%    No improvement                                     right forearm              after 5 weeks                               4      Plaque below                                                                              DMSO     0.5%  Complete clearing                                  right knee                 after one week;                                                               treatment then                                                                terminated and                                                                some recurrence                                                               after 5 weeks.                              5      Large plaque                                                                              DMSO     3%    Fifty percent                                      on left                    improvement                                        forearm                    after 2 weeks                                                                 with almost                                                                   complete clearing                                                             after 4 weeks.                              ______________________________________                                         .sup.1 Weight percent.                                                        .sup.2 Treatment began with DMSO base, after 3 weeks base switched to cor     oil. The corn oil base caused irritation.                                

Referring to Table 1, the effectiveness of the composition of thepresent invention in treating patients with psoriasis is illustrated.Bis-trimethylsilyl-6-aminonotinamide in varying concentrations in a baseof either dimethyl sulfoxide (DMSO) or Aquaphor (A). No adverse sideeffects were observed in any of the treatments, aside from minorirritation when a corn oil base was tried.

Although the best mode contemplated for carrying out the presentinvention has been herein shown and described, it will be appreciatedthat variations and modifications may be made without departing fromwhat is regarded to be the subject matter of the present invention.

What is claimed is:
 1. A trialkylsilyl-6-aminonicotinamide having thefollowing formula: ##STR5## wherein: R is an alkyl group and all threeof said alkyl groups contain no more than 24 carbon atoms; andn and mare 0 to 2 and at least one of n and m is
 1. 2. A compound as in claim1, wherein each R has from 1 to 4 carbon atoms.
 3. A compound as inclaim 1, wherein each R is methyl.
 4. A compound as in claim 1, whereineach R is ethyl.
 5. A compound as in claim 1, wherein each R is propyl.6. A compound as in claim 1, wherein each R is isopropyl.
 7. A compoundas in claim 1, wherein each R is butyl.
 8. A compound as in claim 1,wherein each R is isobutyl.
 9. A compound as in claim 1, wherein each Ris tertiary butyl.
 10. A compound as in claim 1, wherein each R is adifferent alkyl group of 1 to 4 carbon atoms.
 11. A compound as inclaims 1-9, wherein both n and m are
 1. 12.Bis-trimethylsilyl-6-aminonicotinamide. 13.Bis-triethylsilyl-6-aminonicotinamide. 14.Bis-t-butylsilyl-6-aminonicotinamide.